RU2208013C2 - Derivatives of 8-substituted=9h-1,3-dioxol[4,5-h][2,3]- benzodiazepine as inhibitors of ampa/kainate receptor, method for their preparing, pharmaceutical composition based on thereof and method of treatment - Google Patents

Abstract

FIELD: organic chemistry, medicine, neurology, pharmacy. SUBSTANCE: invention relates to novel derivatives of 8-substituted-9H-1,3-dioxol[4,5-h] [2,3] benzodiazepine of the formula (I)

, method for preparing these compounds and pharmaceutical compositions comprising these active substances. Compounds of the formula (I) inhibit AMPA/kainate receptors. In compound of the formula (I) X means carbonyl or methylene group; Y means hydrogen atom or methyl group or in common with R³ it forms valence bond; R¹-R³ mean values as given in the invention claim. Invention relates also to method of treatment of patients with epilepsy or neurodegenerative diseases. Invention provides preparing novel compounds eliciting the curative effect that allows to use them in medicine. EFFECT: improved preparing method, valuable medicinal properties of compounds and composition. 13 cl, 5 tbl

Description

 Description text in facsimile form (see graphic part). T T

Claims (13)

1. The derivative of 8-substituted-9H-1,3-dioxole / 4,5-h // 2,3 / benzodiazepine of the formula I

where X is a carbonyl or methylene group;
R ¹ is a hydrogen atom, a hydroxy group, a C _1-4 alkoxy group, a C _1-4 alkanoyloxy group, a (C _1-4 alkyl) sulfonyloxy group or a group of the formula —NR ⁴ R ⁵ , where R ⁴ and R ^{5 are} , independently of one another, a hydrogen atom, a C _1-4 alkoxy group, a C _1-4 alkanoyl or C _1-6 alkyl group, the latter being substituted by a saturated or unsaturated five- or six-membered heterocyclic group containing 1 or 2 nitrogen atoms or a nitrogen atom and an oxygen atom in as a heteroatom, or N- / phenyl- (C _1-4 alkyl) / - N- (C _1-4 alkyl) amino group in which the phenyl group PPA can be substituted with 1 to 3 substituent (s), which is (are) a C _1-4 alkoxy group, or R ⁴ and R ⁵ form with an adjacent nitrogen atom and possibly another nitrogen atom or atom saturated or unsaturated oxygen of a five to ten membered heterocyclic group, or
X forms with R ^{1 a} cyano group, a tetrazolyl group, a group of the formula —CHNOH or a group of the formula —COR ⁶ , where R ⁶ is a hydroxy group, a C _1-4 alkoxy group, a phenoxy group, a naphthoxy group or an amino group, and the amino group may be substituted with a C _1-4 alkyl group ;
R ² is a nitro group, an amino group or a (C _1-4 alkanoyl) amino group;
R ³ is a hydrogen atom, a C _1-4 alkyl group or a group of the formula -COR ⁷ , where R ⁷ is a hydrogen atom, a C _1-6 alkyl group, a C _1-6 alkyl group substituted by 1-3 halogen atoms, C _{1- 4} alkoxygroup, phenoxygroup, pyridyl group, phenyl group or naphthyl group, and the last two groups can be substituted by 1-3 substituents, or a group of the formula - (CH ₂ ) _n -NR ⁸ R ⁹ where R ⁸ and R ⁹ mean independently from each other, a hydrogen atom, a C _1-4 alkyl group which may be substituted by a phenyl group or a saturated five- or six-membered a heterocyclic group containing one nitrogen group or a nitrogen and oxygen group, and the phenyl group may be substituted with 1 to 3 substituent (s), which (s) is (are) a C _1-4 alkoxy group, or R ⁸ and R ⁹ together with an adjacent nitrogen atom and possibly with another nitrogen atom or an oxygen atom form a saturated or unsaturated five- or six-membered heterocyclic group which may be substituted by a phenyl group which may be substituted by 1-3 substituents selected from the group consisting from a halogen atom or a C _1-4 alkoxy group, n is 0, 1 or 2;
Y is a hydrogen atom or a methyl group, or Y forms a valence bond with R ³ between the carbon atom at position 8 and the nitrogen atom at position 7,
provided that 1) if Y is a hydrogen atom or forms together with R ^{3 a} valence bond and X is a methylene group, then R ^{1 is} not a hydrogen atom, and 2) if Y is a hydrogen atom or a methyl group, and R ³ is C _{1-4 by} an alkyl group or a group of the formula —COR ⁷ , then X is not a methylene group,
and its pharmaceutically acceptable acid addition salts, and its quaternary ammonium derivatives. 2. The derivative of 8-substituted-9H-1,3-dioxol- / 4,5-h // 2,3-benzodiazepine according to claim 1, where X is a carbonyl or methylene group, and R ¹ is a hydrogen atom, a hydroxy group, a methoxy group, an acetoxy group, a methylsulfonyloxy group or a group of the formula —NR ⁴ R ⁵ , where R ⁴ and R ⁵ are independently a hydrogen atom, a methoxy group, an acetyl group or a C _1-4 alkyl group, the latter being optionally substituted with morpholinyl or N - (dimethoxyphenylethyl) -N- (methyl) amino group, or R ⁴ and R ⁵ form with the adjacent nitrogen atom and possibly a further od their nitrogen atom or an oxygen atom a saturated or unsaturated five - devyatichlennuyu heterocyclic group, or X forms together with R ¹ a cyano group, a tetrazolyl group or a group of the formula -CHNOH, R ² is nitro or amino, R ³ is a hydrogen atom or an acetyl group, Y is a hydrogen atom, or Y forms together with R ³ a valence bond between the carbon atom in position 8 and the nitrogen atom in position 7, with the proviso that 1) if Y is a hydrogen atom or forms together with R ³ a valence bond and X is a methylene GRU Sing, then R ¹ is not a hydrogen atom, and 2) if Y is a hydrogen atom or a methyl group and R ³ is a C _1-4 alkyl group or a group of the formula -COR ^7, then X is not a methylene group, and pharmaceutically acceptable acid addition salts and quaternary ammonium derivatives thereof.  3. 5- (4-aminophenyl) -9H-1,3-dioxole / 4,5-h // 2,3-benzodiazepine-8-carboxylamide, 5- (4-aminophenyl) -8-cyano-9H-1 , 3-dioxol / 4,5-h // 2,3-benzodiazepine, 5- (4-aminophenyl) -8- (5-tetrazolyl) -9H-1,3-dioxol / 4,5-h // 2 , 3-Benzodiazepine and their pharmaceutically acceptable acid addition salts, and their quaternary ammonium derivatives. 4. The derivative of 8-substituted-9H-1,3-dioxol- / 4,5-h // 2,3-benzodiazepine according to claim 1, where R ³ is a hydrogen atom or a group of the formula —COR ⁷ , where R ⁷ is a hydrogen atom, a C _1-4 alkyl group, a C _1-4 alkyl group substituted by 1-3 halogen atoms, or a group of the formula - (CH ₂ ) _n -NR ⁸ R ⁹ where R ⁸ and R ⁹ mean independently other, a hydrogen atom, a C _1-4 alkyl group which may be substituted with a phenyl group or morpholinyl, wherein the phenyl group may be substituted with one or two methoxy groups, or R ⁸ and R ⁹ form together with the adjacent atom azo and possibly with another nitrogen or oxygen atom, a saturated or unsaturated five- or six-membered heterocyclic group which may be substituted by a phenyl group, wherein the phenyl group may be substituted by a halogen atom or a methoxy group, n is 0, 1 or 2, X forms together with R ¹ a cyano group or a group of formula -COR ⁶ where R ⁶ is hydroxy or amino, Y is a methyl group, R ² is nitro, amino or (C _1-4 alkanoyl) amino group, and pharmaceutically acceptable salts adjunction of the connections acids. 5. The derivative of 8-substituted-9H-1,3-dioxol- / 4,5-h // 2,3-benzodiazepine according to claim 4, where R ³ is a hydrogen atom or a group of the formula —COR ⁷ , where R ⁷ is a hydrogen atom, a C _1-4 alkyl group, a C _1-2 alkyl group substituted with a chlorine atom, a trifluoromethyl group, a trichloromethyl group or a group of the formula - (CH ₂ ) _n —NR ⁸ R ⁹ where R ⁸ and R ⁹ mean independently from each other, a hydrogen atom, a C _1-2 alkyl group which may be substituted by a phenyl or morpholinyl group, wherein the phenyl group may be substituted by two methoxy groups, or R ⁸ and R ⁹ together with an adjacent nitrogen atom and possibly with another nitrogen atom or an oxygen atom, a pyridinyl, pyrrolidinyl, morpholinyl or piperazinyl group, the piperazinyl group being substituted by a fluorophenyl or methoxyphenyl group, n is 0.1 or 2, X forms together with R ^{1 is a} cyano group, R ² is an amino group or a (C _1-4 alkanoyl) amino group, Y is a methyl group, and its pharmaceutically acceptable acid addition salts. 6. The derivative of 8-substituted-9H-1,3-dioxol- / 4,5-h // 2,3-benzodiazepine according to claim 5, where R ² is an acetylamino group or a propionylamino group, R ¹ , R ³ , X and Y such as described in claim 5, and its pharmaceutically acceptable acid addition salts. 7. The method of obtaining 8-formyl-5- (4-nitrophenyl) -9H-1,3-dioxol- / 4,5-h // 2,3-benzodiazepine of the formula II

which belongs to the group of compounds of formula I, and its pharmaceutically acceptable acid addition salts, and its quaternary ammonium derivatives, characterized in that 8-methyl-5- (4-nitrophenyl) -9H-1,3-dioxol- / 4,5- h // 2,3-benzodiazepine is reacted with an oxidizing agent, and, if necessary, the resulting compound of formula I, where R ² is a nitro group, R ¹ , R ³ , X and Y are as specified in formula I, are converted into a compound formula I, where R ² is an amino group, by reduction, and, if necessary, the resulting compound of formula I, where R ² is an amino group, R ¹ , R ³ , X, and Y, as indicated in formula I, are reacted with a C _1-4 alkanecarboxylic acid or its reactive acylating derivative, and, if necessary, the resulting base of formula I is converted into a pharmaceutically acceptable acid addition salt or isolated from an acid addition salt, and, if necessary, the resulting compound of formula I or a pharmaceutically acceptable acid addition salt thereof is converted to a quaternary ammonium derivative. 8. A pharmaceutical composition having inhibitory activity against AMPA / kainate receptor containing, as an active ingredient, an 8-substituted-9H-1,3-dioxol- / 4,5-h // 2,3-benzodiazepine derivative of the formula I

where X, Y, R ¹ , R ² and R ³ are as specified in claim 1,
or a pharmaceutically acceptable acid addition salt thereof or a quaternary ammonium derivative thereof in admixture with one or more conventional carriers. 9. The pharmaceutical composition of claim 8, containing as an active ingredient a derivative of 8-substituted-9H-1,3-dioxol- / 4,5-h // 2,3-benzodiazepine of the formula I, where X, Y, R ¹ , R ² and R ³ are as defined in claim 2, or a pharmaceutically acceptable acid addition salt thereof, or a quaternary ammonium derivative thereof.  10. The pharmaceutical composition according to claim 8 or 9, containing as an active ingredient one of the following compounds: 5- (4-aminophenyl) -9H-1,3-dioxol / 4,5-h // 2,3-benzodiazepine- 8-carboxylamide, 5- (4-aminophenyl) -8-cyano-9H-1,3-dioxol / 4,5-h // 2,3-benzodiazepine, 5- (4-aminophenyl) -8- (5- tetrazolyl) -9H-1,3-dioxole / 4,5-h // 2,3-benzodiazepine or a pharmaceutically acceptable acid addition salt thereof or a quaternary ammonium derivative thereof. 11. The pharmaceutical composition of claim 8, containing as an active ingredient a derivative of 8-substituted-9H-1,3-dioxol- / 4,5-h // 2,3-benzodiazepine of the formula I, where X, Y, R ¹ , R ² and R ³ are as specified in claim 4, or a pharmaceutically acceptable acid addition salt thereof. 12. The pharmaceutical composition according to claim 11, containing as an active ingredient a derivative of 8-substituted-9H-1,3-dioxol- / 4,5-h // 2,3-benzodiazepine of the formula I, where X, Y, R ¹ , R ² and R ³ are as defined in claim 5, or a pharmaceutically acceptable acid addition salt thereof. 13. A treatment method that includes administering to a patient suffering especially from epilepsy or a neurodegenerative disease, or who is in a post-stroke state, a non-toxic dose of an 8-substituted-9H-1,3-dioxol- / 4,5-h // 2 derivative, 3-benzodiazepine of formula I

where X, Y, R ¹ , R ² and R ³ are as specified in claim 1,
or a pharmaceutically acceptable acid addition salt thereof, or a quaternary ammonium derivative thereof.

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